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Micropillar arrays as a high-throughput screening platform for therapeutics in multiple sclerosis

Nature Medicine volume 20, pages 954–960 (2014)Cite this article

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An Author Correction to this article was published on 12 July 2024

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Abstract

Functional screening for compounds that promote remyelination represents a major hurdle in the development of rational therapeutics for multiple sclerosis. Screening for remyelination is problematic, as myelination requires the presence of axons. Standard methods do not resolve cell-autonomous effects and are not suited for high-throughput formats. Here we describe a binary indicant for myelination using micropillar arrays (BIMA). Engineered with conical dimensions, micropillars permit resolution of the extent and length of membrane wrapping from a single two-dimensional image. Confocal imaging acquired from the base to the tip of the pillars allows for detection of concentric wrapping observed as 'rings' of myelin. The platform is formatted in 96-well plates, amenable to semiautomated random acquisition and automated detection and quantification. Upon screening 1,000 bioactive molecules, we identified a cluster of antimuscarinic compounds that enhance oligodendrocyte differentiation and remyelination. Our findings demonstrate a new high-throughput screening platform for potential regenerative therapeutics in multiple sclerosis.

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Figure 1: Conception and fabrication of micropillar arrays for modeling myelination.
Figure 2: BIMA.
Figure 3: High-throughput screening of bioactive compounds for differentiation and membrane wrapping identifies a cluster of antimuscarinic compounds.
Figure 4: Validation of clemastine and benzatropine with purified oligodendroglia cultured alone or with purified DRG neurons.
Figure 5: Clemastine enhances the kinetics of remyelination and promotes remyelination in mice after gliotoxic injury with lysolecithin.

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Acknowledgements

We thank the Multiple Sclerosis Research Group at the University of California, San Francisco (UCSF) for support, advice and insightful discussions. This work was supported by the US National Multiple Sclerosis Society Harry Weaver Neuroscience Scholar Award (JF 2142-A2/T), UCSF CTSI Catalyst Award for Innovation, gifts from friends of the Multiple Sclerosis Research Group at UCSF and the Joint Research Fund for Overseas Chinese Young Scholars (NSCF, 31228011). The rabbit monoclonal antibody to PDGFRα was a gift from W.B. Stallcup (Sanford Burnham Medical Research Institute).

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  1. Feng Mei and Stephen P J Fancy: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Neurology and Program in Neuroscience, University of California, San Francisco, San Francisco, California, USA

    Feng Mei, Stephen P J Fancy, Yun-An A Shen, Edna Miao, Seonok Lee, Sonia R Mayoral, Stephanie A Redmond, Ainhoa Etxeberria, Ari Green, Stephen L Hauser & Jonah R Chan

  2. Department of Pediatrics, University of California, San Francisco, San Francisco, California, USA

    Stephen P J Fancy

  3. Department of Histology and Embryology, Chongqing Key Laboratory of Neurobiology, Third Military Medical University, Chongqing, China

    Jianqin Niu & Lan Xiao

  4. Cambridge Stem Cell Institute and Department of Veterinary Medicine, Wellcome Trust Medical Research Council, University of Cambridge, Cambridge, UK

    Chao Zhao & Robin J M Franklin

  5. Trianja Technologies, Allen, Texas, USA

    Bryan Presley

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Contributions

F.M., S.P.J.F., Y.-A.A.S., J.N., C.Z., E.M., S.L. and J.R.C. performed experiments. F.M., S.P.J.F., B.P., L.X., R.J.M.F., S.L.H. and J.R.C. provided reagents. F.M., S.P.J.F., S.R.M., S.A.R., A.E., R.J.M.F., A.G., S.L.H. and J.R.C. provided intellectual contributions. F.M., S.P.J.F. and J.R.C. analyzed the data and wrote the paper.

Corresponding author

Correspondence to Jonah R Chan.

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The authors declare no competing financial interests.

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Mei, F., Fancy, S., Shen, YA. et al. Micropillar arrays as a high-throughput screening platform for therapeutics in multiple sclerosis. Nat Med 20, 954–960 (2014). https://doi.org/10.1038/nm.3618

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